Motor neurons directly control muscle activity throughout the body. Motor neuron fibers that extend from the spinal cord to the muscle transmit neural impulses. Motor neuron cell bodies lie within gray matter, the inner core of the spinal cord. They are confined to the anterior horn, one of three distinct functional regions of gray matter. The motor neuron cell bodies receive signals primarily from neurons contained in the other two regions of gray matter. These neurons transmit signals from the brain and other regions of the spinal cord.
Spinal muscular atrophy (SMA) is a fatal neurodegenerative disorder that specifically affects motor neurons of the anterior horn. Extensive loss of these neurons results in progressive muscle weakness and paralysis leading to muscular atrophy. SMA is an autosomal recessive disorder that occurs once in every 6000 live births and has a carrier frequency of 1 in 40. Cystic fibrosis is the only fatal autosomal recessive disorder that occurs with greater frequency. SMA afflicts children, and three types of SMA have been classified based on age of onset and clinical course of the disease. Type I, also called infantile SMA or Werdnig-Hoffman disease, is the most severe form with onset before six months of age and death from respiratory failure by two years of age. Type II, also called chronic childhood SMA or intermediate SMA, presents at around 18 months of age and progresses slowly. Afflicted children cannot walk unaided but survive beyond four years of age. Type III, also called Wohlfart-Kugelberg-Welander disease, is the mildest form with onset ranging from two years of age to adolescence and variable degrees of muscular weakness. (Lefebvre, S. et al. (1995) Cell 80:155-165.)
SMA is caused by lesions in the survival motor neuron (SMN) gene on chromosome 5q13. (Burglen, L. et al. (1996) Genomics 32:479-482.) The normal chromosome 5 contains a duplication of the SMN locus, resulting in a telomere proximal SMN gene (SMN.sup.T) and a centromere proximal SMN gene (SMN.sup.C). The two genes are nearly identical in nucleotide sequence, and both encode a 294-amino acid protein of 38 kilodaltons. However, the SMN.sup.C RNA transcript can also be alternatively spliced, and the resultant protein is truncated at the C-terminus. The function of this alternative protein product is unknown. Molecular genetic analysis indicates that in over 98% of patients with SMA, SMN.sup.T is completely or partially deleted. In the remaining 2%, SMN.sup.T contains point mutations or alterations in splice site consensus sequences. In addition, the severity of the lesion in SMN.sup.T is correlated with the clinical severity of SMA. These data indicate that SMN.sup.T, and not SMN.sup.C, plays a critical role in the determination of SMA. (Lefebvre, S. et al. supra.) However, some studies indicate that the activity of SMN.sup.C may modulate the clinical severity of SMA as previously established by defects in SMN.sup.T. (Coovert, D. D. et al. (1997) Hum. Mol. Genet. 6:1205-1214.) In general, detection of lesions in SMN.sup.T may provide the basis for definitive prenatal and childhood diagnosis of SMA.
Quantitative western analysis shows that SMN protein is normally expressed at high levels not only in the spinal cord, but also in the kidney, liver, and brain. Intermediate SMN levels are detected in skeletal and cardiac muscle, and low levels are detected in primary fibroblasts and lymphoblasts. The role, if any, for SMN outside of the spinal cord is unclear, as the pathology of SMA is specific to motor neuron muscle control. (Coovert et al. supra.) At the cellular level, immunocytochemistry demonstrates that SMN is localized to both the cytoplasm and the nucleus. SMN is diffusely distributed throughout the cytoplasm, while nuclear SMN is concentrated at discrete foci. These foci, called gems, are novel structures that are intimately associated with coiled bodies. Coiled bodies are subnuclear structures involved in RNA processing and metabolism. An in vivo screen for SMN-interacting polypeptides identified fibrillarin, a known component of coiled bodies, and the RGG RNA-binding motif of hnRNP U, a nuclear protein involved in RNA processing. These data suggest that the molecular basis of SMA may involve defects in RNA processing in motor neurons. (Liu, Q. and Dreyfuss, G. (1996) EMBO J. 15:3555-3565.)
The mouse homolog of SMN has been cloned and localized to chromosome 13 in a region syntenic to that of human chromosome 5q13. Unlike human SMN, mouse SMN (mSMN) is a single-copy gene, suggesting that duplication of the human locus is a recent evolutionary event. mSMN encodes a 288-amino acid protein that shares 82% amino acid identity with human SMN. Northern analysis shows that mSMN RNA is widely expressed in various tissues, including heart, brain, kidney and testis. (Viollet, L. et al. (1997) Genomics 40:185-188.) Homozygous deletion of mSMN is lethal during the morula (16-64 cell) stage of embryogenesis. This phenotype is much more severe than that of SMA in humans, suggesting that differences in gene copy number may influence the severity of the SMA phenotype. In humans, SMN.sup.C may partially compensate for deletion of SMN.sup.T to delay disease onset and prolong survival. (Schrank, B. et al. (1997) Proc. Natl. Acad. Sci. USA 94:9920-9925.)
The discovery of a new human SMN-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, treatment, and prevention of neurological, reproductive, and cell proliferative disorders.